The citation of art provided in the present application is not an admission that the art is prior art to the claimed invention.
Hyper-proliferative cell growth contributes to different disorders such as autoimmune associated disorders, atherosclerosis, and cancers. The compounds leflunomide (also known as 5-methylisoxazole-4 carboxylic acid-(4-trifluromethyl)-anilide) and N-(4-trifluoro-methylphenyl)-2-cyano-3-hydroxycrotonamide have been said to be useful in inhibiting hyper-proliferative cell growth. Leflunomide acts as a prodrug for the in vivo formation of N-(4-trifluoro-methylphenyl)-2-cyano-3-hydroxycrotonamide.
According to the abstracts of Kommerer F-J, et al., U.S. Pat. No. 4,284,786 (1981) and Kommerer F-J, et al., U.S. Pat. No. 4,351,841 (1982), leflunomide: . . . has antirheumatic, antiphlogistic, antipyretic and analgesic action, and can be used for the treatment of multiple sclerosis.
Heubach, U.S. Pat. No. 4,087,535 (1978) indicates that leflunomide has anti-inflammatory and analgetic properties.
Robertson S. M. and Lang L. S., European Patent Application 0 413 329 A2 (published 1991) which is concerned with 5-methylisoxazole-4-carboxylic acids that encompass leflunomide, asserts:
The present invention is directed to methods for treating ocular diseases with immune etiology through the use of 5-methyl-isoxazole-4-carboxylic acid anilides and hydroxyethlidene-cyano acetic acid anilide derivatives. In addition the compounds are useful for treating ocular manifestation associated with systemic diseases with immune etiology. The compounds exhibit immunosuppressive, antiinflammatory, and mild antiallergic activity and are useful for the treatment of eye diseases such as uveitis (including rheumatoid nodules), retinitis, allergy (vernal keratocon junctivitis and allergic or giant papillar conjunctivitis) and dry eye (Sjogren's syndrome). Additionally the compounds are useful for prolonging graft survival of corneal or other ocular tissue and are useful as surgical adjuncts in patients which are atopic or immune impaired.
The abstract of Barlett R. R. et al., entitled "Isoxazole-4-Carboxamides and Hydroxyalklidene-Cyanoacetamides, Drugs Containing These Compounds and Use of Such Drugs" PCT/EP90/01800, asserts:
Isoxazole-4-carboxamide derivatives and hydroxyalkylidene-cyanoacetamide derivatives are suitable for the treatment of cancer diseases. These compounds can be prepared by prior art methods. Some of them are new and are suitable, in addition, for the treatment of rheumatic diseases.
Bartlett et al., U.S. Pat. No. 5,268,382 (1993), mentions the use of leflunomide and N-(4-trifluoro-methylphenyl)-2-cyano-3-hydroxycrotonamide to combat chronic graft-versus-host diseases, and in particular systemic lupus erythematosus. Bartlett R. R. et al., Agents and Actions 32:10-21 (1991), indicates leflunomide was shown to be very effective in preventing and curing several autoimmune animal diseases.
Other publications concerning leflunomide include the following; Barlett et al., Leflunomide: A novel immunomodulating drug in: Nonsteroidal Anti-Inflammatory Drugs (2nd ed.) pp. 349-366, Eds. Lewis and Furst, Dekker, N.Y., N.Y.; Pharmaprojects, PJB Publications Lts, Richmond, Surrey, U. K.; Hoechst Present Future Plans, in: R & D Focus Drug News, Oct. 3, 1994; Hoechst Licensing and R & D update, in: R & D Focus Drug News, Feb. 10, 1992; Leflunomide, in: R & D Focus Drug News, May 23, 1994; Xiao et al., Transplantation 58:828-834, 1994; Xiao et al., Transplantation 26:1263-1265, 1994; McChesney et al., Transplantation, 57:1717-1722, 1994; Bartlett et al., Springer Semin. Immunopathol., 14:381-394, 1993; Nichterlein et al., Immunol. Infect. Dis. 4:18-22, 1994; Williams et al., Transplantation, 57:1223-1231, 1994; Weithmann et al., entitled "Use of Leflunomide for the Inhibition of Interleukin 1.alpha," EP 6077742 A2, 940727; Weithmann et al., entitled "Use of Leflunomide for the Inhibition of Interleukin 1.beta," EP 607775 A2, 940727; Weithmann et al., entitled "Use of Leflunomide for the Inhibition of Tumor Necrosis Factor .alpha. (TNF-.alpha.)," EP 607776 A2, 940727; Weithmann et al., entitled "Use of Leflunomide for the Inhibition of Interleukin 8," EP 607777 A2, 940727; Ju et al., Yaoxue Xuebao 92:90-94, 1994; Weithmann et al., Agents Actions, 41:164-170, 1994; Ju et al., Zholigguo Yaoli Xuebao, 15:223-226, 1994; Chong et al., Transplantation, 55:1361-1366, 1993; Zielinski et al., Agents Actions, 38: (Special Conference Issue) C80-C82, 1993; Chong et al., Transplant. Proc., 25:747-749, 1993; Williams et al., Transplant. Proc., 25:745-746, 1993; Schorlemmer et al., Transplant. Proc., 25:763-767, 1993; Glant et al., Immunopharmacology, 23:105-116, 1992; Ulrich et al., Transplant. Proc., 24:718-719, 1992; Ogawa et al, Clin. Immunol. Immunopathol., 61:103-118, 1991; Kuechle et al., Transplant. Proc., 23:1083-1086, 1991; Ogawa et al, Agents Actions, 31:321-328, 1990; and Thoenes et al., Int. J. Immunopharmacol., 11:921-929, 1989.
These references mentioned in the background section are each hereby incorporated by reference herein into the present application.